Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles

天然产物大环化合物的化学酶法合成、作用方式及进化 天然肽大环化合物是有希望的下一代治疗剂，这是由于它们能够结合至 具有挑战性的蛋白质靶点，如蛋白质界面和转录因子。我们实验室的目标是 从天然产物生物合成的见解和化学，以促进新的发现和发展， 天然产物类肽大环化合物。我们将使用化学和酶法相结合的方法， 合成和有效的实验室进化高度受限的肽大环化合物，类似于 自然在今后五年中，这些努力将分为两个主要项目领域。在第一个项目中， 我们将利用酶从核糖体肽的天然产物生物合成途径来修饰mRNA 展示肽文库。这项工作的关键将是显示耦合分析的持续发展 用于阐明酶混杂性的酶修饰。在第二个项目领域， 文库将用于选择针对一组集中的治疗靶点的新型大环肽抑制剂 和复合物。靶向配体复合物的结构表征将揭示大环化合物的原理 参与和阐明针对这些具有挑战性的接口的新策略。这项工作是 有望为开发基于肽大环的治疗剂提供新的途径和技术。

Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles Natural peptide macrocycles are promising next-generation therapeutics, due to their abilities to bind to challenging protein targets, such as protein interfaces and transcription factors. The goal of our lab is to use insights and chemistries from natural product biosynthesis to facilitate the discovery and development of new natural product-like peptide macrocycles. We will use a combined chemical and enzymatic approach for synthesis and efficient benchtop evolution of highly constrained peptide macrocycles similar to those used in nature. Over the next five years, these efforts will be divided between two main project areas. In the first project area, we will use enzymes take from ribosomal peptide natural product biosynthetic pathways to modify mRNA display libraries of peptides. Essential to this work will be the continued development of display-coupled assays for enzyme modification that will be used to elucidate enzyme promiscuity. In the second project area, these libraries will be used to select novel macrocyclic peptide inhibitors against a focused set of therapeutic targets and complexes. Structural characterization of target-ligand complexes will uncover principles of macrocycle engagement and elucidate new strategies for targeting these otherwise challenging interfaces. This work is expected to yield new avenues and technologies for development of peptide macrocycle-based therapeutics.